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Diet-microbe interactions modulating host energy balance

饮食-微生物相互作用调节宿主能量平衡

基本信息

批准号：
9976879
负责人：
Jordan Adam Bisanz
金额：
$ 13.58万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9976879
关键词：
Acute Disease Adult Advisory Committees Affect Americas Animals Antibiotics Award Bile Acid Biosynthesis Pathway Bile Acids Body Weight decreased Body fat Caloric Restriction Calories Cell Culture Techniques Cell physiology Centers for Disease Control and Prevention (U.S.)Child Clostridium difficile Communicable Diseases Communities Data Development Diagnostic Diet Dietary Intervention Disease Ecology Energy Intake Energy Metabolism Environment Environmental Risk Factor Gastrointestinal tract structure Genetic Transcription Germ-Free Gnotobiotic Goals Health Human Individual Infection Intervention Intestines Knock-out Link Macronutrients Nutrition Measures Metabolic Metabolic Diseases Metabolism Metagenomics Methodological Studies Methods Microbe Modeling Monitor Mus Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Organism Organoids Pathogenesis Pathogenicity Phase Phenotype Play Population Positioning Attribute Prevention Public Health Quality of life Reproduction spores Research Role Shotguns Stroke Structure System Testing Toxic effect Toxin Training United States Work antibiotic-associated diarrhea base bile acid metabolism clinical practice combinatorial cost design energy balance experimental study fecal transplantation glucose tolerance gut microbiome gut microbiota heart disease risk host-microbe interactions human subject humanized mouse in vitro Model intestinal epithelium intestinal homeostasis member metabolomics microbial microbial community microbiome microbiome research microbiota mouse model mutant new therapeutic target novel novel therapeutic intervention nutrient absorption nutrition pathobiont pathogen post-transplant programs reconstruction skills uptake weight maintenance

项目摘要

PROJECT SUMMARY/ABSTRACT Obesity affects approximately 35% of adults and 17% of children in the United States increasing the risks of heart disease, stroke and type 2 diabetes. The human gut microbiota, the trillions of microbes that inhabit the gastrointestinal tract, have been implicated as an environmental factor linked to obesity and energy balance; however, the mechanisms are not fully understood. Diet remains the first line intervention to induce weight loss, but its impact on the microbiota, and how this may affect weight loss and regain remain unclear. My preliminary results from a very-low calorie diet intervention in human subjects reveal that caloric restriction induces antibiotic-like disturbances in microbiota composition and function. Fecal transplant from post-diet humans to germ-free mice induces weight loss. Analysis of both human and mouse microbiotas revealed that the diet-induced reconfiguration of the microbiota allowed for expansion of Clostridioides [Clostridium] difficile, best known as a major cause of antibiotic-associated diarrhea and its severe complications. In a colonization model, C. difficile was sufficient to drive weight loss, reduce body fat, and increase glucose tolerance without causing acute disease. These observations have led to the hypothesis that diet interactions with the gut microbiota and C. difficile disrupt nutrient uptake contributing to energy imbalance. The first aim of these studies will focus on the ability of C. difficile to affect host energy balance while characterizing the mechanisms through which it occurs. Preliminary data strongly implicates the C. difficile toxins TcdA and/or TcdB. Using combinatorial and individual knockouts, the causative toxin will be identified and its effects on host energy balance will be extensively characterized. To define the mechanisms through which C. difficile acts at the level of the intestinal epithelium, the effect of sub-toxic purified toxin(s) on nutrient absorption and cell physiology will be examined in organoid models of both the human and mouse intestine. Finally, the ability of asymptomatic colonization to counter diet-induced obesity will be examined. The second aim of this work will examine the mechanism through which caloric restriction affects C. difficile permissibility. Specifically, this aim will test the hypothesis that caloric restriction depletes microbes that produce C. difficile-inhibitory secondary bile acids. Through a humanized mouse model of caloric restriction, and sequence-guided isolation and metabolic characterization, synthetic communities will be designed replicating diet-responsive microbes to specifically test the role of secondary bile acid biosynthesis, and potentially identify new antagonistic interactions which are of great relevance to C. difficile treatment and prevention. The proposed experiments in these aims will leverage my expertise in the microbiome field with new training in obesity and metabolic disease research. An expert interdisciplinary advisory committee, and an institutional focus on microbiome and metabolism research, will provide the ideal environment for the proposed scientific and professional development leading to the creation of an independent research program.

项目总结/文摘